Poorly soluble drug substances have been formulated in pharmaceutically acceptable carriers by finely dividing them, by grinding, into nanoparticles having an effective average particle size of less than 400 nm in order to achieve satisfactory bioavailabiity. However, to keep the nanoparticles from coagulation various surface active agents were used. Such agents may not be desirable and they also reduce the overall amount of the drug which otherwise could be contained in an effective dosage formulation.
Solid dispersions have also been used to increase the dissolution rate and bioavailability of drugs that are poorly water soluble. The carriers used have been physiologically inert compounds that are readily water soluble, such as polyethylene glycols. Two techniques which have been used to prepare solid dispersions are the fusion technique and the solvent technique. In the fusion technique, the drug substance is dissolved in a molten carrier and the mixture cooled to form a solid. In the solvent technique, drug substance and carrier are dissolved in a solvent, followed by removal of the solvent by evaporation or freeze drying.
The preparation of solid dispersions featuring good pharmaceutical properties is difficult. Problems which frequently occur during preparation include: degradation of drug substance at the temperature of the molten carrier; reaction of the drug with the molten carrier; and incomplete solidification of the product, e.g., the carrier remaining largely amorphous. Solid dispersions prepared from esters of p-aminobenzoic acid and xylitol are disclosed, for example, by Sirenius et al., J. Pharm. Sci., 66, No. 6, Jun. 1979.
The present invention is directed to pharmaceutical formulations containing poorly soluble drug substances and particularly to SR 48692 which has shown considerable promise as an NT-antagonist for the treatment of psychosis. SR48692 and a method for the preparation thereof are described by Boigegrain et al in U.S. Pat. No. 5,420,141 (Example 13). SR48692 has the structural formula: ##STR1##
SR48692 has proven to be unusually difficult to formulate into pharmaceutical compositions, due in part to its very low solubility, even in organic solvents.
PCT/US87/02629 discloses a solvent system for enhancing the solubility of an acidic, basic or amphoteric pharmaceutical agent to produce a concentrated solution suitable for soft gelatin capsule filling. The solvent system comprises polyethylene glycol containing 0.2-1.0 mole equivalents of an ionizing agent per mole equivalent of pharmaceutical agent and 1-20% water. Attempts to formulate SR48692 in such a solvent system were not successful.
Sheen et al. in Int. J. Pharm., 118(2), 221-7, 1995, disclose a solid dispersion of a poorly water-soluble drug, RP69698 prepared by a melting method with water-soluble carriers in which RP69698 is highly soluble. When incorporated into a solid dispersion, the formulation contains PEG 3350, Transcutol and Labrasol.